Friday, February 15, 2013

Diamyd (GAD65) is a protein which is one of the targets of the autoimmune attack that starts off type-1 diabetes. It was developed with the idea that giving it to people with type-1 diabetes would teach their immune systems to not attack their own beta cells. It would be like giving someone who is allergic to peanuts, just a tiny amount of the peanut protein that triggered their allergy, in the hopes that they would build up tolerance.

Unfortunately, although it worked in mice and (to some degree) in phase-II studies in people, it failed in phase-III studies in newly diagnosed type-1 diabetics. There are still a couple of smaller on going studies. For example, to see if Diamyd will help prevent type-1 in high risk people who have not yet been diagnosed with the disease.

So that brings us to this study. The idea behind it is:

Give more Diamyd vaccine than was given in the past. About twice as much.

The Vitamin D is supposed to stimulate the part of the immune system that reacts to the Diamyd vaccine, so it makes for a more powerful vaccination effect.

The Ibuprofen ("Advil") lowers the inflammation in the pancreas, which may help save beta cells, and may help the vaccine work better, and may do both.

The study will include 60 children (aged 10 to 18) in the honeymoon phase. They will be followed for 30 months, but expect some results after only 6 months. The participants will be divided into 4 groups of 15. One will be a placebo group, and the other three will each get different combinations of the three treatments. Since they hope to start in February 2013, I think it is reasonable to expect the 6 month results in the second half of 2015 and the 30 month results by the end of 2017. That's assuming it takes them 2 years to recruit 60 people. I have not yet seen a clinical trials record for this, yet.

This study has not yet started recruiting, but when it does, it will be a 66 person trial. It is double blind and placebo controlled. It is open to honeymooners (first 100 days), including children. They hope to start in April 2013 and end by April 2017. I"m not sure of the details, but I think patients will take a pill daily for the first year. They will have clinic visits monthly for the first year, and twice a year thereafter.

Imatinib is a relatively new cancer drug, which is popular because it targets an enzyme that only cancer cells have, so it is relatively non-toxic to non-cancer cells. (The buzzword is "targeted".) The obvious question is why would it be expected to work on type-1 diabetes. The work done so far in mice suggests that it is a different pathway entirely, which leads to it's effect against type-1.

So far, there is no evidence that Vitamin D can cure or treat type-1 diabetes, and only a little evidence that it can prevent the disease. This trial is trying to cure or treat type-1 diabetes by giving Vitamin D during the honeymoon phase.

The trial is being done in Nationwide Children's Hospital (Columbus, Ohio, USA) by Dr.Kathryn J Stephens and Dr. Robert P Hoffman. It has not started enrollment, but they plan to enroll 54 people. Half will get vitamin D for 9 months, half will get a placebo. They hope to have results in March 2014.

I had previously reported on a vitamin D trial, but that was a population based trial, not an intervention trial. This is an intervention trial, which are typically much higher quality.

I know that some people are very emotional about saying "a person who has type-1 diabetes" vs. saying "a type-1 diabetic", as in "they gave the drug to five people with type-1 diabetes" vs. "they gave the drug to five type-1 diabetics". Some people object strongly to the second form, because they think that it defines the person by the disease; that it signals in some way that the disease is the person or the person is the disease.

Personally, I usually use the first form, because I prefer it and because I know that some people really object to the second form. But I'm not fanatical about it, and you will occasionally see me refer to "type-1 diabetics". I'm not trying to insult anyone when I use the second form.

Friday, February 1, 2013

These two news updates are both interesting, and each probably deserves it's own blog entry. However, since I'm backlogged, I'm putting them together in one posting (together with a Zhao update). Even after this posting, I'm still a month or more behind.

Results from a Polish Trial of Polyclonal Tregs

What is being tested? I call this technique "Polyclonal Tregs", but I'm not sure if it has a more official name. Basically, the researchers remove one specific type of T regulator cell (called a "CD3(+)CD4(+)CD25(high)CD127(-)" T regulator) from a person with type-1 diabetes. They use these cells to grow a lot more of these cells outside of the body, and then put them back in the body. Since regulatory T cells naturally regulate the body's immune system, the hope is that they will prevent the autoimmune attack which causes type-1 diabetes. Previous research in both animals and people has supported the idea that increasing regulator T cells may be a path to a cure.

The Polish group tested this technique on 10 recently diagnosed (within 2 months) type-1 patients and compared them to 10 patients who did not get the treatment. 4 people got a lower dose (10 × 10^6 Tregs/kg) and 6 people got a high dose (twice as much). In my opinion, they packed a lot of research into a small trial. However there were no differences between the lower dose group and the higher dose group.

Because it was an early trial, safety was an important consideration, and there were no safety related issues. So that was good. The publication had effectiveness data from a short (four month) follow up. Basically:

The treated patients generated about 50% more C-peptide than untreated.

The treated patients used about half the injected insulin as untreated.

But remember, these people were within 2 months of diagnosis, and even at the end of the data presented here, were within 7 months of diagnosis, so well within the common honeymoon timeframe. So I think longer follow on is critical to understanding how important these results are. If these patients are still using half the insulin that untreated patients are using after 2 years, that would be wonderful.

The good news right now is that they already have one year follow up data, and expect to get it published later in 2013. Beyond that, they have some improvements to the protocol, and hope to start a follow on trial with an updated protocol soon.

This trial has now enrolled its first two groups (out of four total). I'm told all subjects are doing well with stable pancreas function. The researchers are currently in the middle of the 3rd group, and they anticipate completing the full study enrollment this year. Each group gets 8 times as large a dose as the previous group so the last group will get about 500 times as much as the first.

... and the Ethics of Experimenting on Children

There is an obvious question here: If both studies started at about the same time, why does one have results 4 years sooner than the other? I think there are two answers to this question. The first is pretty simple: the Polish researchers published data covering 4 months after treatment. The American researchers are gathering data for years. But that only explains about 20 months of difference.

The second reason might be more important: The American researchers are only enrolling adults, people over 18 years old. The Polish researchers enrolled children, 5-18 years old. Obviously, when you are looking for recently diagnosed type-1 diabetics, there are a lot more to be found in the 5-18 year range than the 18+ year range. By limiting recruitment to adults, the Americans have a much smaller pool of people, and it will therefore take them much longer to fully populate their trial.

But why are the American researchers only enrolling adults? That answer is a combination of ethics and previous experience. There is a general ethical principal (enshrined in various FDA rules, and international guidelines) that research should be done on adults first, before it is done on children, if that is feasible. That makes a lot of sense, of course, but here we see the impact. For a disease like type-1 diabetes, it is possible to recruit recently diagnosed adults, but it is far harder and slower. So if we insist that the first bunch of patients are adults, it serves to slow down research disproportionately.

The Polish group had previously run a similar clinical trial in adults with a different disease (graft vs. host disease). Now measuring safety in adults with one disease is not exactly the same as measuring safety in adults with a different disease, but it is similar. Therefore, they could recruit children based on the safety profile with adults in the previous study. Also, they could test different doses more quickly, again based on the previous experience.

One way to view the immune system is a balancing act. We want aggressive immune cells to attack foreign cells, but overly aggressive cells might attack our own beta cells and cause type-1 diabetes. So we also want regulatory immune cells to keep the aggressive cells in line. But we don't want those cells too strong, because then they would prevent an attack on the foreign cells. In this view, type-1 diabetes can be seen as a too aggressive immune system, and therefor boosting the regulatory side might be a cure.

The regulatory cells which are been grown out (or "amplified" might be a better word) are general purpose regulatory cells. That's a good place to start, but it would be even better if the researchers could multiply a regulatory cell that specifically targeted autoimmune cells (the "bad" cells that are attacking the wrong target). Unfortunately, the technology is not there yet, although people are working on it. But in any case, we need to start somewhere.

Below is a link to a study that suggests that newly diagnosed type-1 diabetic children have lower levels of these T regulator cells, than children who do not have type-1 diabetes. (Although it was a small group.) http://www.ncbi.nlm.nih.gov/pubmed/19454187

A Note About "Remission"

Some type-1 researchers use the term "remission". Specifically, they use it to mean "Uses less than 1/2 a unit of insulin per kg of body weight per day". Don't be confused. Non-researchers think of "remission" as meaning "doesn't use insulin", but that is NOT how researchers use the term. If your child weighs 40 kg (about 88 pounds), and uses 20 units of insulin, or less, then they are "in remission", and this does happen to some people during the honeymoon.

Dr. Claresa Levetan at Perl Bioscience has filed the paperwork to start two very interesting studies. Both studies are looking at a combination of Cyclosporine and Lansoprazole (commonly known as "Prevacid") as a cure for type-1 diabetes. The two studies are identical, but one recruits honeymooners and the other established type-1 diabetics. These are combo clinical trials exactly like many people have been hoping for, for years: Cyclosporine is known to stop the autoimmune attack and Lansoprazole is known to encourage the natural regrowth of pancreatic beta cells. Both are approved drugs (for other diseases). Lansoprazole (as "Prevacid") is over the counter, so has a very good safety profile. Cyclosporine has a more complex safety profile. I'm sure if this study pans out, the relative safety of Cyclosporine is going to be an important topic of discussion.

Both studies are expected to enroll 200 people (half getting the treatment and half getting placebo). They plan to start in September 2013 and end by March 2014 (so very quick). There will be four groups: one group getting both drugs, one just getting Cyclosporine, one just getting Lansoprazole, and one getting neither. This is good experimental design for a two drug combination. They will measure C-peptide in response to eating, A1c, and insulin usage.

Note on phases: The researchers running this trial have described it as a "phase-III trial", however I consider it a phase-II trial. Why the difference? For me, size is the most important issue. At 200 people, it is right on the border between what I consider phase-II and phase-III for clinical trials aimed at curing type-1 diabetes. (For comparison, all eight recent phase-III trials have involved 300 people. That seems to be the magic number for FDA approval as a pivotal trial in type-1 diabetes.) Also, this combination of drugs has never (to my knowledge) been tested on type-1 diabetics before. Since both drugs are approved for other things, I'm willing to call it phase-II (rather than phase-I), but with zero experience with the combination, I'm not willing to call it a phase-III.

Of course, the important question is not what I consider the trial, or even what the researchers consider the trial, the real question is how will the FDA consider the trial? That remains to be seen, but remember: since both drugs are already approved for other uses, your doctor can prescribe this combination right now. It would be an off label use.

The researcher working on this, Dr. Claresa Levetan, previously worked on CureDM, and sold that to Sanofi-Aventis two years ago. My understanding is that they are developing the CureDM technology (a peptide which stimulates beta cell development) for the type-2 market.

The basic summary is that the clinical trial in Spain has started. Two patients had their first session of stem cell educator therapy in December 2012. The plan is to treat a total of 30 people. (Not sure how many are placebo and how many will get the real treatment.) The two treated so far have had type-1 for over 10 years. This trial is expected to end in September 2014, but we will not know with certainty until it is fully enrolled.

JDCA State of the Cure 2012

The JDCA (Juvenile Diabetes Cure Alliance) is trying to focus more research dollars into cure research (as opposed to treatment research, cause research, etc.) They publish research papers, which are often quite interesting. They use my blog as a source, and we sometimes discuss various research issues.

The article below is their year end summary, and well worth a read. Although I certainly don't agree with everything in it, it is a rich source of information. (I especially object to their not including Dr. Zhao's research as a possible cure, and JDCA did cover Zhao in a report after this one.)

In the past, I have included a specific "thank you" when people reviewed a blog posting, provided information for it, or pointed out the news to me (when only one person did so). Unfortunately, keeping track of who helped with what, and also making sure it was OK to thank them by name, has become too much of a burden.
So I'm going to stop doing that.

I'm very sorry I will not be able to thank people individually for their help in writing this blog. But I do want to thank:

My wife, who improves my English, and puts up with the hours I spend yelling at the computer when I should be talking with her.

All the researchers who have answered my questions and provided extra information.

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This blog discusses cures and preventatives for type-1 diabetes that are either in human trials or just about to start. Treatments for diabetes are not generally discussed here, unless they can turn into a cure or a preventative. My definition of a cure is this:1. Blood sugar control without testing and with doctor's visits 4 times a year, or less. Any cure must result in an average lifespan close to normal.2. Does not require a lifetime of immunsuppressive drugs, so it is not trading one treatment for another. (but a couple of operations, or a short course of drugs is OK)Obviously, this is my personal definition of a cure; yours may differ.Because a cure for type-1 diabetes is likely to involve a combination of several different drugs or treatments, I try to follow research into anything which may be an important part of the cure.

My Non-Conflict of Interest Statement

I don't work for a company involved in medical research; I never have.

I don't get paid in any way by any company doing medical research; I never have. And that includes free samples, free travel, or free anything. I do sometimes participate in market research studies or focus groups, and they sometimes pay.

None of the hours that I have put into my blog, or the posts that I make to any web site, has ever been paid for. (Except for some very nice and heart felt thank-you emails, and those are worth more than money.)

My daughter has type-1 diabetes and participates in clinical trials. I sometimes report on trials that she participates in, but I do not reveal her participation because I consider her medical history to be private.

I sometimes "beta test" new software or devices involved in type-1 diabetes. When I'm blogging about something where I have been given special access, I say so.

In the past I have volunteered with JDRF, The NIIB Project, and I currently am a fellow with JDCA. JDRF and NIIB Project was completely unpaid. JDCA has given me equipment that I use to help my blogging.

Over the years my daughter has used several types of insulin, several types of meters, and pumps made by different manufacturers. I don't always mention if I'm blogging about a company who's products she uses now or in the past (there are so many).